Based on our murine data, we developed a phase 1 and 2 protocol employing alemtuzumab, 400cGy total body irradiation (TBI) and escalating doses of post-transplant cyclophosphamide (PT-Cy) ranging from 0mg/kg in cohort 1 and 50mg/kg in cohort 2 to 100mg/kg in cohort 3. A total of 21 patients with sickle cell disease and 2 patients with beta thalassemia were transplanted and had complications including cirrhosis, pulmonary hypertension, heart failure, and end-stage renal disease. The engraftment rate improved from 1/3 (33%) in the first cohort, to 5/8 (63%) in the second cohort to 10/12 (83%) in the third cohort. Percentage of donor myeloid and CD3 chimerism also improved with subsequent cohorts. Overall survival is 78.3%; 3 died after return of their sickle cell disease. There was no mortality before 100 days post-transplant. At present, 0% in the first cohort, 25% in the second cohort, and 50% in the third cohort remain free of their disease. There was no Grade 2-4 acute or chronic extensive graft-versus-host disease (GVHD). Therefore, we have shown that PT-Cy improves engraftment in patients with SCD who are at high risk for early mortality. As we have reached stopping rules for the study, we recently opened a new protocol which has added additional immunosuppression in an attempt to improve the success rate. Since June 2017, 6 patients have been transplanted. Five patients remain engrafted and are doing well. One of the 5 developed Grade 2 acute GVHD which responded well to steroids. The 6th patient was a patient who rejected her graft on the first protocol and died from an intracranial hemorrhage about 60 days post transplant. Additional patients are now being recruited and our next transplant will occur on 8/31/18. We will also search for early biomarkers associated with graft rejection in an attempt to identify graft rejection at an early and potentially more reversible state and explore mechanisms of engraftment and tolerance induction.